Mouse cytotoxic T cell-derived granzyme B activates the mitochondrial cell death pathway in a bim-dependent fashion
Resumen: Cytotoxic T cells (Tc) use perforin and granzyme B (gzmB) to kill virus-infected cells and cancer cells. Recent evidence suggests that human gzmB primarily induces apoptosis via the intrinsic mitochondrial pathway by either cleaving Bid or activating Bim leading to the activation of Bak/Bax and subsequent generation of active caspase-3. In contrast, mouse gzmB is thought to predominantly induce apoptosis by directly processing pro-caspase-3. However, in certain mouse cell types gzmB-mediated apoptosis mainly occurs via the mitochondrial pathway. To investigate whether Bim is involved under the latter conditions, we have now employed ex vivo virus-immune mouse Tc that selectively kill by using perforin and gzmB (gzmB+Tc) as effector cells and wild type as well as Bim- or Bak/Bax-deficient spontaneously (3T9) or virus-(SV40) transformed mouse embryonic fibroblast cells as targets. We show that gzmB+Tc-mediated apoptosis (phosphatidylserine translocation, mitochondrial depolarization, cytochrome c release, and caspase-3 activation) was severely reduced in 3T9 cells lacking either Bim or both Bak and Bax. This outcome was related to the ability of Tc cells to induce the degradation of Mcl-1 and Bcl-XL, the anti-apoptotic counterparts of Bim. In contrast, gzmB+Tc-mediated apoptosis was not affected in SV40-transformed mouse embryonic fibroblast cells lacking Bak/Bax. The data provide evidence that Bim participates in mouse gzmB+Tc-mediated apoptosis of certain targets by activating the mitochondrial pathway and suggest that the mode of cell death depends on the target cell. Our results suggest that the various molecular events leading to transformation and/or immortalization of cells have an impact on their relative resistance to the multiple gzmB+Tc-induced death pathways.
Idioma: Inglés
DOI: 10.1074/jbc.M114.631564
Año: 2015
Publicado en: JOURNAL OF BIOLOGICAL CHEMISTRY 290, 11 (2015), 6868-6877
ISSN: 0021-9258

Factor impacto: 4.258 (2015)
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 71 / 289 = 0.246 (2015) - Q1 - T1
Financiación: info:eu-repo/grantAgreement/ES/MINECO-FEDER/SAF2011-25390
Financiación: info:eu-repo/grantAgreement/ES/MINECO/SAF2008-02139
Tipo y forma: Artículo (Versión definitiva)
Área (Departamento): Inmunología (Departamento de Microbiología, Medicina Preventiva y Salud Pública)
Área (Departamento): Bioquímica y Biología Molecular (Departamento de Bioquímica y Biología Molecular y Celular)
Área (Departamento): Microbiología (Departamento de Microbiología, Medicina Preventiva y Salud Pública)

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Exportado de SIDERAL (2017-05-03-14:22:37)

Este artículo se encuentra en las siguientes colecciones:
Artículos > Artículos por área > Bioquímica y Biología Molecular
Artículos > Artículos por área > Microbiología
Artículos > Artículos por área > Inmunología

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